It has been possible to show that compounds of the present invention are outstanding inhibitors of the sodium-hydrogen exchanger (NHE), especially the sodium-hydrogen exchanger of the subtype-3 (NHE-3).
The NHE-3 inhibitors known to date derive, for example, from compounds of the acylguanidine type (EP825178), norbornylamine type (WO0144164), 2-guanidino-quinazoline type (WO0179186) or benzamidine type (WO0121582, WO0172742). Squalamine, which has likewise been described as an NHE3 inhibitor (M. Donowitz et al., Am. J. Physiol. 276 (Cell Physiol. 45): C136-C144), according to the current state of knowledge, does not act immediately like the compounds of the formula I but rather via an indirect mechanism and thus attains its maximum intensity of action only after one hour.
Tetrahydroisoquinolines as inhibitors of the sodium-hydrogen exchanger of the subtype 3 (NHE3) have already been described in the patent application WO03048129, WO2004085404 and German application No. 102004046492.8. The patent application WO03055880 describes the related compound class of the tetrahydroisoquinolinium salts as NHE3 inhibitors. It has now been found that, surprisingly, the compounds of the formula I described here likewise constitute potent inhibitors of the NHE3 and have advantageous pharmacological and pharmacokinetic properties.
The NHE-3 is found in the body of various species, preferentially in the gall bladder, the intestines and in the kidneys (Larry Fliegel et al., Biochem. Cell. Biol. 76: 735-741, 1998), but has also been found in the brain (E. Ma et al., Neuroscience 79: 591-603).
Owing to their NHE-inhibitory properties, the compounds of the present invention are suitable for the prevention and treatment of disorders which are caused by an activation of or by an activated NHE, and also of disorders which have the NHE-related damage as a secondary cause.
The compounds of the invention can also be used for the treatment and prevention of disorders in which the NHE is only partially inhibited, for example by use of a lower dose.
The use of the inventive compounds relates to the prevention and to the treatment of acute and chronic disorders in veterinary and in human medicine.
As a consequence of their pharmacological actions, the compounds of the formula I are especially suitable for improving the respiratory drive. They can therefore be employed for the treatment of disturbed respiratory states, as can occur, for example, in the event of the following clinical states and disorders: disturbed central respiratory drive (for example central sleep apneas, sudden infant death, postoperative hypoxia), muscular-related respiratory disorders, respiratory disorders after long-term ventilation, respiratory disorders in the course of adaptation in high mountains, obstructive and mixed forms of sleep apneas, acute and chronic pulmonary disorders with hypoxia and hypercapnea.